Cannabinoids and Cancer

Overview:  The use of cannabinoids in treating the side effects of cancer chemotherapy is more widely-studied than many other potential therapeutic applications, and a number of clinical studies have taken place investigating the use of THC and synthetic cannabinoids as anti-emetic agents.  Two preparations have been licensed for use in clinical treatment either in the UK or elsewhere, including dronabinol (synthetic THC) and Nabilone (a novel synthetic cannabinoid). 

Side effects of chemotherapy and wasting diseases:  The powerful drugs used in cancer chemotherapy effectively kill reproducing cells, including both the malignant tumour cells and also, as a side effect, many cells continually reproducing such as hair follicle cells and those lining the gut, leading to severe nausea & vomiting.  These side effects can be very severe and many patients find these difficult or impossible to tolerate, falling into a wasting syndrome through malnutrition brought on by a combination of reduced appetite and poor gastrointestinal efficiency, which can itself shorten life expectancy. 

There is variation between the effects of different anti-cancer drugs.  Cisplatin, one of the most effective chemotherapy agents, induces vomiting in over 99% of patients not taking an antiemetic, with around 10 vomiting episodes per dose, although methotrexate causes emesis in under 10% of patients [1] [2] [3]  

There are also variations in the efficacy and side effects between conventional drugs used to treat nausea and vomiting.  The BMA [4] listed the side effects of commonly-used anti-emetic drugs as follows:

(a)     Phenothiazines (prochlorperazine, haloperidol) - severe dystonic reactions, drowsiness, dry mouth, blurred vision, urinary retention, hypotension (low blood pressure), allergic reactions, occasional jaundice.

(b)     Metoclopramide - acute dystonic reactions, facial and muscle spasms, drowsiness, restlessness, diarrhoea, depression

(c)     Domperidone - acute dystonic reactions

(d)     SSRAs (Ondansetron, gransisetron) - constipation, headache, altered liver function. [5]

The main beneficial effects reported from use of cannabinoids are a reduction in the incidence and severity of nausea and vomiting (emesis), and stimulation of appetite, together reducing the severity of cachexia - wasting syndrome - in patients receiving chemotherapy treatment.

Jamshidi & Taylor [6] discovered "intrahypothalamic anandamide initiates appetite by stimulation of CB1 receptors, thus providing evidence on the involvement of hypothalamic endocannabinoids in appetite initiation."  Inui [7] concluded "cannabinoids... act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life."

In a 2003 review, Croxford [8] noted "Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease", similarly, Walsh et al [9] noted "The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia."  Grotenhermen [10] agreed "Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells." Parker et al [11] concluded "endogenous cannabinoids play a role in modulation of nausea". Zurcher [12] recommended cannabinoids for treatment of cancer-induced anorexia.

However Taskhin et al warned "The potential for marijuana smoking to predispose to the development of respiratory malignancy is suggested by several lines of evidence, including the presence of potent carcinogens in marijuana smoke and their resulting deposition in the lung, the occurrence of premalignant changes in bronchial biopsies obtained from smokers of marijuana in the absence of tobacco, impairment of antitumor immune defenses by delta9-tetrahydrocannabinol, and several clinical case series in which marijuana smokers were disproportionately over represented among young individuals who developed upper or lower respiratory tract cancer. Additional well designed epidemiological and immune monitoring studies are required to determine the potential causal relationship between marijuana use and the development of respiratory infection and/or cancer."  and Russmann et al [13] reported a case history of a patient suffering a fatal stroke after smoking cannabis during a session of cisplatin chemotherapy for testicular cancer. In a general review, Drewe [14] noted "Chronic marijuana smoking is associated with increased toxicity and the risk of cancer of the respiratory tract. There is evidence of disturbance of the immune system and teratogenic effects of chronic cannabis use".  Gardner et al [15] found methanandamide "resulted in an increased rate of tumor growth" in mouse lung cells, but noted "methanandamide augments tumor growth by a cannabinoid receptor-independent pathway"

Clinical Trials involving THC:  Sallan et al (1975) [16] found 10mg THC Æsignificantly more effectiveà than placebo at reducing nausea and vomiting in 22 chemotherapy patients.  Chang et al [17] (1979) found 10mg oral or 17mg smoked THC to decrease methotrexate-induced nausea and vomiting compared to placebo in 14 of 15 patients.  Frytak et al [18] found 15mg THC better than placebo at inhibiting prochorperazine-induced emesis, but noted some of the 116 gastrointestinal cancer patients to find the side effects (sedation, Æhighà dysphoria, hypotension & tachycardia) intolerable.  Orr & McKearnan [19]   found 7mg THC to be more effective than prochlorperazine and placebo in 55 patients, of which 82% reported a high.  Lucas & Laszlo [20]   found 15mg or 2x5mg THC more effective than placebo or standard regimes. 

However Chang et al [21]   found 3-hourly oral (10mg) or smoked (17.4mg) THC ineffective compared with placebo in a small study of 8 patients receiving adriamycin and cyclophosphamide.  Niedhart et al [22] compared THC and Haloperidol in 52 chemotherapy patients finding no difference in efficacy between the two drugs.  Gralla et al [23] found 10mg THC more effective than placebo, but less effective than metoclopramide in controlling cisplatin-induced vomiting in a 27-patient study.  Ungerleider et al [24]   in a large study of 214 patients, found 4-hourly 7.5-12.5mg THC and 10mg prochlorperazine equally effective in reducing nausea and vomiting, but noted THC was preferred by more patients.  Lane et al [25] found significant improvement both with THC (10mg dronabinol) and prochlorperazine, and the combination more effective than either alone in abolishing nausea and vomiting in 62 patients.

Clinical Trials involving Nabilone:  Nagy et al [26] studied 47 patients receiving cisplatin, finding nabilone more effective than prochlorperazine or placebo in reducing nausea & vomiting caused by cisplatin.  Herman et al [27] found similar results with 113 patients receiving cisplatin, cyclophosphamide & mustine therapy.  Einhorn et al [28] studied 100 chemotherapy patients, finding nabilone significantly more effective than prochlorperazine and preferred by 75% of patients, but noted lethargy and hypotension, similar results found in studies of 114 patients by Wada et al [29] , in 36 patients by Levitt et al [30] , 18 patients by Johannson et al [31] , 26 patients by Ahmedzal et al [32] and 24 patients by Niranan & Mattison [33] . 

Jones et al [34] found Æsignificant reduction in nausea and vomiting with nabilone compared to placeboà in a study of 54 patients and noted acceptable side effects to include dizziness (65%) and drowsiness (51%).  Niederle et al [35] found nabilone significantly better than alizapride in reducing cisplatin-induced nausea & vomiting in 20 patients.   Pomeroy et al [36] found nabilone superior to domperidone in reducing vomiting episodes among 38 patients, as did Dalzell et al [37] in a study of 23 children, finding that despite more side effects it was preferred by two thirds of respondents, and a study of 30 children by Chan et al [38] found nabilone superior to prochlorperazine.

Studies involving natural cannabis:  Vinciguerra et al [39] studied 56 cancer patients unresponsive to conventional antiemetic agents, who were asked to rate the effectiveness of marijuana compared to prior chemotherapy cycles.  Smoked marijuana was rated as "moderately effective" or "highly effective." by 78% of patients.  The authors concluded that marijuana had antiemetic efficacy, but no control group was used and the patient population varied with respect to prior marijuana use or THC therapy.

A double-blind, cross-over, placebo-controlled study by Levitt et al [40] compared smoked marijuana with oral THC among 20 patients receiving a variety of chemotherapy drugs. The efficacy was similar, with 25% of patients achieving complete control over vomiting. Seven patients (35%) indicated apreference for oral THC over marijuana; 4 patients (20%) preferred smoked marijuana and 9 patients (45%) expressed no preference.

Neither study investigated the time course of antiemetic control, advantages of self-titration with the smoked marijuana, or ability of patients to swallow the pills. Patients with severe vomiting are unlikely to be able to swallow or keep pills down long enough for them to take effect.  The onset of drug effect is much faster with smoked THC in cannabis than it is for oral delivery [41] [42] [43] , and the differences in cannabinoid content of smoked cannabis compared to the oral THC route can alter the users perceptions and subjective effects.  Haney et al [44] reported smoked cannabis to make users feel Æmellowà whereas oral THC did not. .  Although many cannabis users claim that smoking the drug provides more effective relief from vomiting than oral THC, no controlled studies have yet been published which firmly establish this to be the case.

Conclusions of Major Recent Inquiries:  The British Medical Association [45]   concluded: 

"Cannabinoids are undoubtedly effective as anti-emetic agents in vomiting induced by anti-cancer drugs"  and that "Systematic trials of the effectiveness of cannabinoids in combatting vomiting resulting from different chemotherapy agents should be carried out".

The United States Institute of Medicine report [46] concluded: 

"In patients already experiencing severe nausea or vomiting, pills are generally ineffective, because of the difficulty in swallowing or keeping a pill down, and slow o nset of the drug effect. Thus an inhalation (but, preferably not smoking) cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced nausea." ... "It is possible that the harmful effects of smoking marijuana for a limited period of time might be outweighed by the antiemetic benefits of marijuana, at least for, patients for whom standard antiemetic therapy is ineffective and who suffer from debilitating emesis. Such patients should be evaluated on a case by case basis"

The House of Lords Science & Technology Select Committee made the following findings and recommendations [47] :

"...cannabis and cannabinoids are likely to be of benefit as anti-emetics only to the small proportion of patients who do not respond to existing treatments, or possibly in the treatment of the delayed stages of emesis which can occur for some days following cancer chemotherapy, and which do not respond well to the serotonin antagonists. Nevertheless, cannabinoids are undoubtedly effective as anti­emetics and more research in this field might explore their use in combination with the serotonin antagonists, help to determine for which patients they are most appropriate, and examine the potential of the allegedly less psychoactive cannabinoid D8­THC, for which there have been encouraging preliminary clinical results"

"Unlike cannabis itself, the cannabinoid THC (dronabinol) and its analogue nabilone are already accepted by the Government as having medical value -- producing the anomaly that, while cannabis itself is banned as a psychoactive drug, THC, the principal substance which makes it psychoactive, is in legitimate medical use. Some of our witnesses are prepared to contemplate wider medical use of the cannabinoids, but not of cannabis itself. We disagree, since some users of both find cannabis itself more effective. We do, however, welcome the inclusion of THC in the trials proposed by the Asscher group, in like-for-like comparison with cannabis itself" 

"Dronabinol (THC), though not licensed in this country, has already been moved to Schedule 2 to the Misuse of Drugs Regulations, and nabilone is a licensed medicine and not a controlled drug; so no Government action is required in either case to permit clinical trials or indeed prescription. ...we recommend that the Government should raise the matter of rescheduling the remaining cannabinoids with the WHO in due course, in order to facilitate research."  

"Our principal reason for recommending that the law be changed, to make legal the use of cannabis for medical purposes, is compassionate. Illegal medical use of cannabis is quite widespread; it is sometimes connived at and even in some cases encouraged by health professionals; and yet at present it exposes patients and in some cases their carers to all the distress of criminal proceedings, with the possibility of serious penalties. We acknowledge that, if our recommendation were implemented, the United Kingdom would be moving out of step with many other countries; we consider that the Government should not be afraid to give a lead in this matter in a responsible way."

Recent scientific developments-anti-tumour activity:  Recent scientific advances in the study of cannabinoid receptors and endocannabinoids have produced exciting new leads in the search for anti-cancer treatments, with CB1 and CB2 agonists (like THC) associated with tumour regression, reduced proliferation and blood supply to tumours, and apoptosis (programmed cell-suicide) among cells of various cancer types.

Blazquez et al [48] reported "Cannabinoids, the active components of marijuana and their derivatives, induce tumor regression in rodents... Inhibition of tumor angiogenesis may allow new strategies for the design of cannabinoid-based antitumoral therapies."  Sanchez et al [49] reported "growth of the rat glioma (one of the most malignant forms of cancer) is inhibited by psychoactive cannabinoids" and that "local administration of (a) selective CB(2) agonist... induced a considerable regression of malignant tumors".

In a study of skin cancers, Casanova et al [50] found "In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors" Furthermore Di Marzo et al [51] noted the "anti-proliferative effect of anandamide in human breast cancer cells" was enhanced by Palmitoylethanolamide.  De Petrocellis et al [52] considered this effect to be mediated by CB1 and vanilloid receptors.  Fowler et al [53] concluded "the antiproliferative effects of anandamide were not solely mediated by either its hydrolysis to produce arachidonic acid or its CB receptor-mediated activation of phospholipase A(2) since palmitoyltrifluoromethyl ketone did not prevent the response to anandamide."

In a study of thyroid cancer cells, Portella et al [54] noted "Stimulation of cannabinoid CB1 receptors ... inhibits the growth of a rat thyroid cancer cell-derived tumor in athymic mice" and concluded "CB1 receptor agonists might be used therapeutically to retard tumor growth in vivo by inhibiting at once tumor growth, angiogenesis, and metastasis"  Mimeault et al [55] , studying prostate cancer, reported "The potent anti-proliferative and cytotoxic effects of (anandamide) on metastatic prostatic cancer cells might provide basis for the design of new therapeutic agents for effective treatment of recurrent and invasive prostatic cancers." Recht et al [56] found a metabolite of THC ajulemic acid (AJA; dimethylheptyl-THC-11-oic acid) to be "a potent anti-inflammatory agent without psychoactive properties... Its very favorable toxicity profile, including lack of psychoactivity, makes it suitable for chronic usage."

Studying the effect of cannabinoid receptor agonists and antagonists on different types of colorectal cancer cells, Ligresti et al [57] found "Anandamide, 2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2 cell proliferation. This effect is blocked by the CB(1) antagonist SR141716A, but not by the CB(2) antagonist SR144528, and is mimicked by CB(1)-selective, but not CB(2)-selective, agonists. In DLD-1 cells, both CB(1) and CB(2) receptors mediate inhibition of proliferation."  Jacobsson et al [58] concluded "the antiproliferative effects of the endocannabinoids upon (rat glioma) cells are brought about by a mechanism involving combined activation of both vanilloid receptors and to a lesser extent cannabinoid receptors"  Gomez del Pulgar [59] et al found THC to cause death of glioma cells due to local synthesis of ceramide, and demonstrated [60] a neuroprotective effect of cannabinoids on astrocytes. 

Gonzalez et al [61] found reduced CB1-receptor activity to be associated with development of pituitary cancers, noting "estrogen-induced pituitary hyperplastia was associated with a marked reduction in CB1 receptors" Pagotto et al [62] found elevated CB1 receptor activity and endocannabinoids in tumorous pituitary gland cells, noting "The results of this study point to a direct role of cannabinoids in the regulation of human pituitary hormone secretion."  Rubovitch et al [63] demonstrated CB1-receptor-agonist modulated stimulation of calcium ion uptake in neuroblastoma cells. Bifulco et al [64] found an analogue of anandamide to inhibit oncogene-mediated tumour growth via CB1-receptor activity.

In a 2002 review. Guzman et al [65] concluded "cannabinoid administration induces regression of malignant gliomas in rodents by a mechanism that may involve sustained ceramide generation and extracellular signal-regulated kinase activation. In contrast, most of the experimental evidence indicates that cannabinoids may protect normal neurons from toxic insults, such as glutamatergic overstimulation, ischaemia, and oxidative damage. Regarding immune cells, low doses of cannabinoids may enhance proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis."  In 2003 Guzman [66] added "Cannabinoids - the active components of Cannabis sativa and their derivatives - exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies."

Parolaro et al [67] concluded "Modulation of the endocannabinoid system interferes with cancer cell proliferation either by inhibiting mitogenic autocrine/paracrine loops or by directly inducing apoptosis; however, the proapoptotic effect of anandamide is not shared by other endocannabinoids and suggests the involvement of non-cannabinoid receptors"  Bifulco & Di Marzo [68] reviewed studies of antitumour activity and concluded "Recently, evidence has accumulated indicating that stimulation of cannabinoid receptors by either THC or the endocannabinoids influence the intracellular events controlling the proliferation and apoptosis of numerous types of cancer cells, thereby leading to anti-tumour effects both in vitro and in vivo. This evidence is reviewed here and suggests that future anti-cancer therapy might be developed from our knowledge of how the endocannabinoid system controls the growth and metastasis of malignant cells."

Hodgkins & Lymphomas:  There are few scientific references specifically to research in Hodgkins disease.  Abrahamov et al [69] reported the effects of a study of delta-8-THC in children suffering from haematological cancers and undergoing chemotherapy, noting "Vomiting was completely prevented. The side effects observed were negligible.".  However Lockwood [70] reported a case history of "Marihuana and alcohol intolerance" in a Hodgkin's disease patient.

In a study of lymphobastomas, McKallip et al [71] found "human tumor cells were also susceptible to apoptosis induced by THC, HU-210, anandamide, and the CB2-selective agonist JWH-015. This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist SR144528 partially reversed the THC-induced apoptosis.  Also, because CB2 agonists lack psychotropic effects, they may serve as novel anticancer agents to selectively target and kill tumors of immune origin." Islam et al [72] noted a "high expression of the cannabinoid receptor 1 (CB1) gene in all Mantle Cell Lymphoma cases analysed"

However Joosten et al [73] postulated that an overabundance of CB2 receptors in transgenic mice may increase predisposition to leukaemia, and Jorda et al [74] concluded "a major function of Cb2 receptor expressed on myeloid leukemia cells or normal splenocytes is stimulation of migration"

Summary -side effects of chemotherapy:  Levitt [75] in an early review presentation, suggested:"The use of cannabinoids as cancer chemotherapy anti-emetics represents, in essence, the use of a drug with a relatively undefined mechanism of action to treat the side effects of other drugs, also with relatively undefined mechanisms of action, which are being used to treat cancer, a disease or series of diseases the precise nature of which remains enigmatic."  Since LevittÃs review, there have been major advances in cannabinoid pharmacology and in understanding of the cancer disease process.  In particular, research by Herkenham et al [76] [77] demonstrated the presence of numerous cannabinoid receptors in the nucleus of the solitary tract, a brain center that is important in the control of vomiting [78] . 

Although other recently developed anti-emetics are as effective or more effective than oral THC, nabilone or smoked cannabis, for certain individuals unresponsive to conventional anti-emetic drugs, the use of smoked cannabis can provide relief more effectively than oral preparations which may be difficult to swallow or be expelled in vomit before having a chance to take effect.  The psychoactive/euphoriant effects of THC or smoked cannabis may provide an improvement in mood, whereas several conventional preparations e.g. phenothiazines such as haloperidol (known as Æmajor tranquillisersà and also used in the treatment of psychoses such as schizophrenia), may produce unwanted side effects such as excessive sedation, flattening of mood, and/or distressing physical Æextrapyramidalà symptoms such as uncontrolled or compulsive movements. A 1991 US survey [79] found public support for marijuana use by cancer patients.

In the USA, synthetic THC (Dronabinol) is available for use as an adjunct to cancer chemotherapy treatment, and in the UK, both the British Medical Association and House of Lords recognised the potential for use of cannabinoids in preventing nausea and vomiting.

Summary -Direct anti-cancer activity of cannabinoids.  Some researchers have investigated the link between mental and spiritual state and cancer remission, associating the cannabinoid system with the expression of pleasure on the one hand and stress on the other.  Lissoni et al [80] reviewed the effect of psychospiritual state on cancer growth or suppression, noting "Stress, anxiety and depressive states are associated with immunosuppression and enhanced frequency of tumors. On the other hand, the states of sexual pleasure and spiritual joy enhance the immune efficacy, by counteracting tumor onset and dissemination. The biochemistry of pleasure and immunostimulation is mainly mediated by pineal indoles and cannabinergic substances, whereas that of stress, anxiety and depression is associated with enhanced production of adrenal steroids, opioids and catecholamines."

There would appear to be growing evidence of direct anti-tumour activity of cannabinoids, specifically CB1 and CB2 agonists, in a range of cancer types including brain (gliomas), skin, pituitary, prostate and bowel.  The antitumour activity has led in laboratory animals and in-vitro human tissues to regression of tumours, reductions in vascularisation (blood supply) and metastases (secondary tumours), as well as direct inducement of death (apoptosis) among cancer cells.  Indeed, the complex interactions of endogenous cannabinoids and receptors is leading to greater scientific understanding of the mechanisms by which cancers develop.

However smoking of cannabis releases a number of non-cannabinoid carcinogens into the lungs and upper respiratory tract, and a number of researchers (notably Tashkin and colleagues) have identified pre-cancerous changes in lung cells.  The failure of these researchers to discover significant evidence of actual cancer cells in the lung may be attributed to these anti-cancer activities of cannabinoids including THC counteracting the effects of other carcinogens in smoked cannabis.

December 2003